Thiamine Deficiency: Pearls and Pitfalls

Authors: Jennifer Reyes, DO (EM Resident Physician, Aventura Hospital and Medical Center) and Annalee Baker, MD (EM Attending Physician / Assistant Program Director, Aventura Hospital and Medical Center) // Edited by: Manpreet Singh, MD (@MPrizzleER – Assistant Professor of Emergency Medicine / Department of Emergency Medicine – Harbor-UCLA Medical Center) and Alex Koyfman, MD (@EMHighAK – EM Attending Physician, UT Southwestern Medical Center / Parkland Memorial Hospital) 

Clinical Case

A 52 year-old man well known to the emergency department is brought in by EMS after he was found intoxicated on a street corner. His vital signs are HR 100 BP 145/90 RR 16 O2 98% T 98.5°F and FS 120 mg/dL. He has no complaints. He is disheveled and malodorous. He has conjunctival injection bilaterally, with horizontal nystagmus at rest. He has a staggering and ataxic gait, and 1+ pitting edema of both legs. He is oriented, and his speech is normal.

He is evaluated by the intern, who in his first 3 months of residency has already cared for this particular patient several times. The intern presents the patient and makes his assessment that the patient is mildly intoxicated. The plan is to observe and reassess him for “clinical sobriety”, at which point he will be discharged, as he has been many times before.

Although thiamine would not be isolated until 1911, the clinical syndrome of thiamine deficiency was recognized as far back as 2700 BC, when the term “beriberi”, meaning “wasted wasted” was first coined in China.¹ Nearly 5,000 years later in the 1800’s, a Japanese naval surgeon discovered that death rates among sailors plummeted when they ate a nutritious and varied diet instead of mainly white rice, but it would still be many years before scientists understood that thiamine was the crucial ingredient lacking in polished rice.¹

In 1881, Carl Wernicke described his eponymous syndrome, based on the symptoms exhibited by a 20 year-old seamstress, who had developed pyloric stenosis and malabsorption after she drank sulfuric acid in a suicide attempt. But the nutritional link would not be understood for 50 more years.² Eventually, a successful international effort to enrich flour with thiamine was launched during the 1940’s, in an attempt to improve the health of the British and American populations while food was rationed and other nutritious foods were scarce. But thiamine deficiency did not completely disappear from the population.

Thiamine is a water-soluble vitamin found in whole grains, meats, eggs, and legumes.³ It is primarily absorbed in the duodenum and proximal jejunum and converted to its active form, thiamine pyrophosphate, a coenzyme essential for carbohydrate metabolism.^3,4 Deficiency in thiamine produces cardiovascular and neurological abnormalities that can be at best, mild and reversible and at worst, permanently disabling or even fatal.

Maximum body stores of thiamine, which exist primarily in skeletal muscle, amount to 30 mg and can be depleted in as little as 20 days in a patient with inadequate intake, malabsorption, or excess metabolic demand.^5,6 Thus, when thiamine is absent from the diet, clinically evident thiamine deficiency typically develops in 2-3 weeks. However, tachycardia, the earliest symptom of thiamine deficiency, can develop as early as 9 days after intake ceases.⁴

Quick Pathophysiology

The multi-organ manifestations of thiamine deficiency can be explained by the essential role of thiamine in the body’s most basic metabolic processes. Thiamine pyrophosphate or thiamine diphosphate is a coenzyme in the pyruvate dehydrogenase complex, which accelerates the conversion of pyruvate to acetyl coenzyme A. This process links anaerobic glycolysis to the aerobic Krebs cycle which produces 36 mol of adenosine triphosphate (ATP) from 1 mol of glucose.

When thiamine is not available to facilitate these reactions, energy production is limited to the comparatively paltry 2 mol of ATP produced via anaerobic metabolism. Thiamine is also a cofactor for alpha-ketoglutarate dehydrogenase (also of the Krebs cycle) and transketolase (of the pentose phosphate pathway) in which essential nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate (NADH and NADPH) are created for use in energy production and reductive biosynthesis.^4,7 Thiamine deficiency therefore results in massive energy deficits and defects in cell synthesis, replication, and repair.³

In the central nervous system, decreased acetylcholine synthesis results in impaired conduction, and mitochondrial dysfunction from oxidative stress leads to neurodegeneration.^3,8 In the peripheral nerve and muscle tissues, this leads to decreased sensorimotor activity, muscle atrophy, and neuropathy.² In cardiac muscle, lack of thiamine shifts pyruvate toward increased lactate production, resulting in a dysfunctional myocardium.¹⁰

Pearls

• No thiamine = no ATP!
• Organs affected are those most dependent on glucose energy production: Nervous system + Cardiovascular system

Who is at Risk?

In the United States, a varied diet and mandatory fortification of foods such as flour used for cereals and bread protect most healthy individuals from thiamine deficiency. But certain factors put patients at risk, and the emergency physician must be attuned to these risk factors in order to recognize the sometimes subtle indications of clinically significant deficiency.

 Alcoholism

If there was a poster child for thiamine deficiency, it would be the patient with alcohol dependence. It is estimated that between 30-80% of heavy drinkers are thiamine deficient due to poor diet, along with impaired GI absorption, storage, and function of thiamine.^7,10

Dietary Deficiency

But the list doesn’t stop there. Other patients with poor oral intake such as those with eating disorders, acquired immunodeficiency syndrome (AIDS), conditions dependent on total parenteral nutrition, cancer and the elderly are also at increased risk.^4,11,12,13 Greater than one-third of patients with anorexia nervosa are thiamine deficient, yet these patients continue to be underdiagnosed.¹⁴ In countries where people consume a diet rich in thiamine antagonists such as raw fish and shellfish, and populations whose diet is mostly based on polished white rice, thiamine deficiency may be seen in otherwise healthy people, however typically in the United States, the patient will have some type of identifiable risk factor.^7,5

Bariatric Surgery

With the incidence of obesity on the rise, the number of patients undergoing bariatric surgery has increased markedly. According to the American Society of Bariatric surgery, the number of bariatric surgeries more than doubled from 2001 to 2003 and in 2014 totaled to 193,000 procedures.^15,16 These patients are particularly vulnerable to thiamine deficiency due to prolonged nutrition with fluids, post-op emesis, low intake, and decreased resorption of thiamine secondary to absent stomach and/or proximal jejunum.³

One study found that 29% of women were already thiamine deficient prior to bariatric surgery .¹⁷ Most patients who developed signs of beriberi manifested at 4-12 weeks post-op and there have been over 100 reported cases of dry beriberi, the neurological form of thiamine deficiency, in this population.^{3, 18} Other gastrointestinal risk factors include hyperemesis, irritable bowel disease, malabsorption syndromes, and nasogastric or PEG tube feeds with inadequate thiamine replacement.^7,10,19

 Increased Metabolic Demand

In addition to patients with poor intake and malabsorption, there are a number of conditions known to increase thiamine demand, which can also precipitate clinical deficiency. Fever, pregnancy, lactation, and hyperthyroidism can all increase demand for thiamine.⁴ Chronic diseases such as systolic heart failure, active malignancy on chemotherapy or end-stage renal disease on hemodialysis are common causes of deficiency.^7,11,20

Heart Failure

A meta-analysis of 9 studies found that thiamine deficiency was more common in heart failure patients compared to controls (OR 2.53, 95% CI 1.65-3.87).²¹ In addition to the disease process itself, heart failure patients may be prone to thiamine deficiency due to their dependence on diuretics, which increase renal elimination of thiamine and deplete stores. Furosemide is particularly notorious because, in addition to increasing clearance, it impairs thiamine uptake in the myocardium.^22,23 In various studies, thiamine supplementation has been shown to improve ejection fraction, urine output, weight loss and signs and symptoms of heart failure, however, it has yet to be tested in a large-scale randomized controlled clinical trial.²⁴

Sepsis

In addition to the commonly recognized risk factor of alcoholism, and the perhaps less commonly known but logically obvious risk factors such as bariatric surgery and chronic illness, another patient who is typically thiamine deficient is the patient in septic shock. Thiamine deficiency is extremely common in sepsis patients and is associated with an increased risk of death.²⁵ Indeed, thiamine has been explored as part of sepsis resuscitation protocols, though its exact role has not been definitively determined.^25,26

Pearls

Patients at Risk for thiamine deficiency:

• Alcohol dependence
• Systolic heart failure (especially those on Furosemide!)
• Chronically ill
• Post-bariatric surgery
• Sepsis

On patient rounds, the intoxicated patient is evaluated by the team. His ataxia and nystagmus is noted, and he is additionally found by Romberg exam to have diminished proprioception. The patient admits he has not eaten any food for several days, and has been ingesting almost exclusively alcohol. During rounds, the attending asks the patient an unusual question:

Attending: “I recognize you! You’re that new pitcher for the Yankees. You pitched a great game last night-very impressive. Go Yanks!”

Patient: “Yeah, it was a rough start, but we did it.”

Attending: “How long have you been playing baseball professionally?”
Patient: “Oh, it’s gotta be about 10 years now. Thinking about retiring.”

The attending suggests that the patient have laboratory studies including a complete blood count and complete metabolic panel performed, and asks the intern if there are any medications he would like to administer at this time. The intern responds, “It’s not even baseball season…”

Patient presentation

The manifestations of thiamine deficiency can be broken down into wet (cardiac) and dry (neurologic) beriberi. Most commonly, patients will have either wet or dry beri beri, but rarely, they can show signs of both conditions simultaneously.²⁷ In the early stages, both types of beri beri are responsive to treatment with thiamine.

Dry beriberi is associated with neurologic abnormalities and is more common in the U.S. than wet beriberi.³ Wernicke’s encephalopathy, or the classic triad of altered mental status, ataxia, and ophthalmologic abnormalities includes elements of dry beri beri, but even in those with Wernicke’s, the entire triad is present in only 20-30% of patients.^3,11,28 Other findings include diminished reflexes, decreased proprioception, muscle pain, and a myopathy that produces weakness and atrophy beginning in the lower extremities and progressing proximally.⁷

Wernicke’s is a clinical diagnosis, and although the full triad is rarely present, diagnostic sensitivity reaches 85% when at least 2 of the following are present: dietary deficiency, ophthalmoplegia, ataxic gait, altered mental status, or memory disturbance.²⁸ Wernicke’s alone carries a 10-20% mortality, and those who survive may be disabled.⁴

Korsakoff psychosis, an irreversible disorder of anterograde amnesia and confabulation, occurs in approximately 80-85% of survivors.^4,7 Given that alcohol intoxication commonly presents with ataxia and altered mental status, early signs of critical thiamine deficiency may often be overlooked in one of the most vulnerable patient populations. Heightened clinical suspicion is critical.

Wet beriberi is associated with high output heart failure and fluid retention caused by vasodilation and the formation of arteriovenous fistulae.^4,20,29 Bedside echocardiogram may show cardiomegaly with dilatation of the right heart.²⁹ Patients may present with lower extremity edema, minor EKG changes, and sometimes no other causes for heart disease.³⁰

Soshin beriberi is an ominous, fulminant and often fatal presentation of thiamine deficiency causing sudden cardiac death.³¹ Apart from an elevated lactate level, all workup may be negative. Cardiovascular disease caused purely by thiamine deficiency may be very rare in the United States, but more commonly, patients with existing CHF may present with worsened exacerbation due to concomitant low levels of thiamine. Biochemical diagnosis is technically possible by testing for erythrocyte transketolase activity, but this test is rarely available and technically difficult.^7,32 Thus the diagnosis is more often empirical.

Pearls

• Wet (cardiac) and dry (neurologic) beri beri: rarely seen together
• Full triad of AMS, ataxia and ophthalmic abnormalities not necessary for diagnosis

The attending explains to the team that this patient has classic signs of both Wernicke’s encephalopathy and of Korsakoff psychosis. He is ataxic, with diminished proprioception and has ophthalmologic abnormalities. Although the patient is oriented x 3, he has subtle deficits in memory and anterograde amnesia. His attempts to agree with and expound upon the fictitious baseball history represent confabulation, a unique and interesting psychological phenomenon wherein the patient attempts to fill in gaps in memory by fabrication in order to hide the damage to their brain.³³

Although many of his exam findings are subtle and could easily be mistaken as alcohol intoxication, the patient is not severely intoxicated, and his history of heavy alcohol use and poor oral intake put him at high risk for severe thiamine deficiency. While waiting for laboratory results, the team confers about how to treat the patient. The intern inquires as to whether there is a laboratory test to quantify his deficiency and confirm the diagnosis.

Treatment

There currently are no readily available laboratory tests to confirm thiamine deficiency in the ED. Thus, when one of the above clinical syndromes is present, treatment is started without lab confirmation. Luckily, the treatment is cheap, effective, and readily available, and rarely produces side effects or adverse reactions.⁴

Acute treatment in the ED is based on rapidly replacing the patient’s thiamine empirically, and replenishing other vitamin and electrolyte deficiencies when confirmed. Thiamine should be administered parenterally, as oral absorption is unpredictable. The intravenous route is preferred over intramuscular administration, as these patients often have low muscle mass and coexistent coagulopathy.⁴

Numerous sources recommend a minimum dose of 100 mg IV as a preventative therapy for asymptomatic but at-risk patients, which will protect the patient for more than one week. The treatment for Wernicke’s encephalopathy is considerably higher at 500 mg of IV thiamine diluted in normal saline TID for 2-3 days, followed by 250 mg daily for 3-5 days, infused over 30 minutes.¹⁰ These patients may ultimately be discharged on 100mg oral thiamine with close follow-up.¹⁰ Treatment of isolated early stage neuropathy can be accomplished with 20-30mg/day.³

Glucose

The question often arises as to whether it is necessary to routinely administer glucose along with thiamine. In patients with hypoglycemia and co-existent but perhaps subclinical thiamine deficiency, the theory is that glucose loading increases demand for thiamine, and given alone, could precipitate Wernicke’s encephalopathy. This is based on four case reports in malnourished patients from 1981.³⁴ However, it is unlikely that this effect will be observed acutely following a single glucose load.

Prolonged glucose administration without thiamine can certainly trigger clinical thiamine deficiency to appear, but this should not preclude a single potentially life-saving dose of glucose in the emergency department.^{35,36,37,38,39} It is prudent to co-administer thiamine to hypoglycemic patients at risk of thiamine deficiency, but treatment of hypoglycemia should not be delayed while waiting for thiamine.⁴

Multivitamins and Magnesium

Nutritional deficiencies of folate, vitamin B6, and vitamin B12 have been associated with thiamine deficiency and the traditional practice has been to replenish these vitamins in the ED whenever thiamine is administered.^10,40,41 Magnesium is a cofactor necessary in order for thiamine to function properly and many patients with alcohol dependence are deficient in magnesium.⁷ However, while treatment with thiamine is a critical intervention that is likely to be effective, the evidence behind empiric treatment with parenteral multivitamins and magnesium is lacking.

In a recent evaluation by Li et al, intoxicated patients were evaluated and serum folate, thiamine, and vitamin B12 levels were tested at the time of presentation.⁴² The authors found that no patient evaluated had a low serum folate level and none were deficient in vitamin B12. In addition, there is no evidence that treatment of folate and vitamin B12 deficiencies, even when confirmed to be present, will result in any rapid or measurable clinical improvement in the emergency department. Additionally, some guidelines recommend against empiric administration of magnesium prior to confirmation of deficiency.⁴³

The evidence for empiric thiamine administration on the other hand is fairly robust, and the appropriate dosing is likely higher than what is typically given. The traditional “banana bag” containing thiamine, folic acid, multivitamins, and sometimes magnesium, typically has a thiamine content of 100 mg of thiamine in 1L of normal saline. This may be sufficient for prevention, but is woefully inadequate as treatment of Wernicke’s encephalopathy, and the additional components of the solution may be unnecessary in the emergency department. There are no documented cases of over treating with thiamine, therefore a liberal treatment approach is appropriate.

Outcomes

After initiation of treatment, clinical improvements can be seen rather quickly. Within 2-3 hours ophthalmoplegia may resolve, followed by ataxia within 2-3 days, and finally, cognitive function return to baseline after 2-3 weeks. Although treatment with thiamine can be extremely effective for some, most patients with Wernicke’s encephalopathy will end up with some form of prolonged or even permanent neurologic impairment.⁴⁴

Pearls

• Treatment for Wernicke’s: 500 mg IV tid for 2-3 days, then 250 mg IV daily 3-5 days
• Don’t delay urgent treatment of hypoglycemia
• Banana bags are unnecessary, and may lead to under-treatment of thiamine deficiency

The patient’s blood work returned, showing a mild megaloblastic anemia, hypokalemia and borderline low magnesium. He was given 500 mg of IV thiamine and a turkey sandwich, and his potassium and magnesium were repleted separately. He was admitted to the ICU for further management of Wernicke-Korsakoff Syndrome. His ataxia and neuropathy improved, and his nystagmus disappeared, but his memory deficits persisted and were still present at discharge, when he was sent home with prescriptions for vitamins and a referral to an alcohol treatment program. 

Future Directions in Thiamine Deficiency

Understanding the variety of patients who are at risk for thiamine deficiency, it may not seem surprising that thiamine has emerged as part of a new resuscitation protocol in sepsis.

Vitamins are depleted in septic patients, in large part due to high metabolic demand.⁴⁵ Vitamin C levels are particularly low in critically ill patients and have been associated with multi-organ failure and death.⁴⁶ Thiamine deficiency has been found in up to a third of septic patients and is associated with increased mortality.⁴⁷

A patient with beriberi may present with profound vasodilation and high output heart failure and require catecholamine support in the form of vasopressors. In addition to its role as a potent antioxidant and maintainer of microcirculation and tight junctions, vitamin C is an integral cofactor in the synthesis of norepinephrine, dopamine, vasopressin, and cortisol.⁴⁸ Severe vitamin C deficiency in and of itself can result in a deranged sympathetic nervous system, and it makes sense that replenishing vitamin C could be beneficial in both beri beri and septic shock.

A recent double-blind RCT found that among septic patients who were found to be thiamine deficient, replacing thiamine caused decreased lactate levels and decreased mortality.²⁵ Finally, although research has shown that steroids alone do not decrease mortality in sepsis, there is evidence to suggest that vitamin C and steroids together work synergistically.^48,49 In sepsis, oxidation of the glucocorticoid receptor prevents cortisol from binding. Administering vitamin C restores glucocorticoid receptor function, and the combination has been found protective against endotoxin.⁵⁰ Thus, the ‘metabolic resuscitation protocol’ was born.

The above pathophysiologic observations and clinical experience treating critically ill patients led Dr. Paul Marik at Eastern Virginia Medical School to develop his ‘metabolic resuscitation protocol’ for sepsis. The study was published in CHEST in 2016 and the EM/critical care world began to buzz about the perhaps too-good-to-be-true results reported by Marik and his team.²⁶

Dr. Marik conducted a retrospective before-and-after clinical study at Sentara Norfolk General Hospital to see if the combination of vitamin C, hydrocortisone, and thiamine reduced mortality in patients with severe sepsis. This was a single center, non-randomized, un-blinded study. Consecutive patients admitted to EVMC from January to July 2016 with a diagnosis of severe sepsis or septic shock received a cocktail of 1.5g IV vitamin C q 6hrs for 4 days or until discharge, 50 mg IV hydrocortisone q 6hrs for 7 days followed by taper for 3 days, and thiamine 200 mg IV q12hrs for 4 days or until discharge. The control arm received standard ICU care plus 50 mg IV hydrocortisone q6hrs for 7 days or until discharge followed by a 3 day taper.

The primary outcome in this study was hospital survival. Secondary outcomes included duration of vasopressor therapy, ICU length of stay, delta serum procalcitonin over 72 hours, delta Sepsis Related Organ Failure Assessment (SOFA) score over 72 hours, and requirement of renal replacement therapy in patients with acute kidney injury (AKI). 94 patients were included in the study, with 47 in each treatment arm.

Hospital mortality in the treatment arm was significantly lower at 8.5% compared to 40.4% in the control group (p < 0.001), corresponding to an absolute risk reduction of 31.9% and a number needed to treat of 4, and the treatment group required significantly less vasopressor therapy (18.3 vs 54.9 hours) and less renal replacement therapy (10% vs. 33%).

This study was the first of its kind to evaluate the combination of vitamin C, hydrocortisone, and thiamine in patients with sepsis.⁵¹ It is hypothesis-generating, and has already inspired multiple RCT’s attempting to duplicate its findings.^52,53 Marik says that he has successfully treated over 300 patients with the “same, reproducible results”, and the cocktail is now being utilized in over 30 medical centers across the globe.⁵⁴ The drugs included in the treatment cocktail are all widely available, cheap, and safe.^51,55 However, the metabolic resuscitation protocol is far from ready for primetime.

To quote Dr. Marik himself, “in the hierarchy of scientific evidence, before and after studies are just above wives tales and anecdotes.”⁵⁶ The study was a small, retrospective, single center, before-and-after study without randomization or blinding. The methodology of this study leaves overwhelming opportunity for conscious and unconscious bias. Even though a propensity-adjusted analysis failed to detect confounding, this tool is less effective at detecting bias in smaller samples sizes, does not account for inherent bias, and is a poor replacement for simple randomization.^57,58 The trial also lacked statistical power to detect side effect, and it might still be too early to detect harm.^51,59

Marik has confirmed the need for an RCT to validate the findings of his study, but also suggests adopting his treatment strategy in the meantime because “you have nothing to lose except a surviving patient.”⁴⁸   Do we have nothing to lose? As Dr. Swaminathan points out, each additional component of our treatment strategy takes time away from other interventions, such as early antibiotics, source control, and fluids.⁵⁸

Pearls

• Thiamine deficiency should be suspected in septic patients, especially if they have other risk factors
• Be on the lookout for future studies of the metabolic resuscitation protocol

Summary

• Have a high suspicion for Wernicke’s encephalopathy, and diagnose if at least 2 of the following are present:
  • Altered mental status
  • Ophthalmologic abnormalities
  • Ataxic gait
  • Dietary deficiency (includes alcoholism)
  • Memory disturbance
• Take a thorough history
  • CHF, AIDS, bariatric surgery, eating disorders, renal disease
  • Medication history: Lasix
  • Social: EtOH abuse
• Exam
  • Look for dependent edema ~ wet beriberi
  • Perform a thorough neurologic exam, looking for
    • Weakness in distal muscles
    • Muscle pain, atrophy
    • Diminished reflexes
    • Symmetric peripheral neuropathy, especially in lower extremities
    • Ataxia
    • Ocular abnormalities
  • Labs
    • Thiamine deficiency is a clinical diagnosis
    • The patient may have metabolic lactic acidosis, megaloblastic anemia, low potassium and magnesium levels
  • Imaging
    • MRI of the brain will show abnormalities in Wernicke’s but is not routinely performed in the ED
    • Bedside echo: look for cardiomegaly and/or dilation of R ventricle = wet beriberi
  • Treatment
    • Prophylaxis: 100mg IV thiamine
    • Treatment of Wernicke’s: 500mg IV thiamine tid 2-3 days, followed by 250 mg daily for 3-5 days
  • Disposition
    • Wernicke’s encephalopathy: Intermediate unit / ICU
    • Other patients on the spectrum of thiamine deficiency: dispo on a case-by-case basis

References / Further Reading

1. Carpenter KJ. Beriberi, white rice and vitamin B: A disease, a cause and a cure. University of California Press, 2000.
2. Victor M, Adams RD, Collins GH. The Wernicke-Korsakoff Syndrome and Related Neurologic Disorders Due to Alcoholism and Malnutrition. 2nd ed. Philadelphia, PA: FA Davis; 1989.
3. Stroh C, Meyer F, Manger T. Beriberi, a severe complication after metabolic surgery – review of the literature. Obes Facts. 2014; 7(4): 246–252. Published online 2014 Jul 30. doi: 10.1159/000366012
4. Nelson LS, Lewin NA, Howland MA, Hoffman RS, Goldfrank LR. Goldfrank’s Toxicologic Emergencies. 10th ed. China: McGraw-Hill Companies, Inc; 2015
5. Sechi GP, Serra A: Wernicke’s encephalopathy: new clinical settings and recent advances in diagnosis and management. Lancet Neurol 2007; 6: 442–455.
6. Antozzi P, Lester C, Soto F, et al: Thiamine deficiency in an obese population undergoing laparoscopic surgery. Surg Obes Relat Dis 2005; 1: 264–265.
7. Bolton, C; Jones, A. Thiamine Deficiency. Student BMJ; London 20 (Dec 2012)
8. Abdou, E.; Hazell, A. Thiamine Deficiency: An Update of Pathophysiologic Mechanisms and Future Therapeutic Considerations. Neurochemical Research, 2015, Volume 40, Number 2, Page 353
9. Chisolm-Straker M, Cherkas D. Altered and unstable: wet beriberi, a clinical review. J Emerg Med. 2013 Sep; 45(3): 341–344. Published online 2013 Jul 10. doi: 10.1016/j.jemermed.2013.04.022
10. Thomson AD. The absorption of radioactive sulphur-labelled thiamine hydrochloride in control subjects and in patients with intestinal malabsorption. Clin Sci 1966; 31: 167-79.
11. Zahr N, Kaufman KL, Harper CG. Clinical and pathological features of alcohol-related brain damage. Nat Rev Neurol, 7 (2011), pp. 284-294
12. Lactic acidosis traced to thiamine deficiency related to nationwide shortage of multivitamins for total parenteral nutrition—United States, 1997. MMWR Morb Mortal Wkly Rep. 1997; 46: 523–538
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27. Eijkman C. Nobel Lecture 1929: Antineuritic Vitamin and Beriberi. http://www.nobelprize.org/nobel_prizes/medicine/laureates/1929/eijkman-lecture.html.

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